Perioperative organ injury remains a medical, social and economic problem in cardiac surgery. Patients with postoperative organ dysfunction have increases in morbidity, length of stay, long-term mortality, treatment costs and rehabilitation time. Currently, there are no pharmaceutical technologies or non-pharmacological interventions that can mitigate the continuum of multiple organ dysfunction and improve the outcomes of cardiac surgery. It is essential to identify agents that trigger or mediate an organ-protective phenotype during cardiac surgery. The authors highlight nitric oxide (NO) ability to act as an agent for perioperative protection of organs and tissues, especially in the heart–kidney axis. NO has been delivered in clinical practice at an acceptable cost, and the side effects of its use are known, predictable, reversible and relatively rare. This review presents basic data, physiological research and literature on the clinical application of NO in cardiac surgery. Results support the use of NO as a safe and promising approach in perioperative patient management. Further clinical research is required to define the role of NO as an adjunct therapy that can improve outcomes in cardiac surgery. Clinicians also have to identify cohorts of responders for perioperative NO therapy and the optimal modes for this technology.